Genetics of hypogonadotropic Hypogonadism—Human and mouse genes, inheritance, oligogenicity, and genetic counseling

Louden, Erica; Poch, Alexandra; Kim, Hyung Goo; Ben‐Mahmoud, Afif; Kim, Soo Hyun; Layman, Lawrence C.

doi:10.1016/j.mce.2021.111334

Cited by 18 publications

(19 citation statements)

References 187 publications

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“…The inheritance in the other pedigrees is consistent with autosomal dominant with variable penetrance and expressivity, a phenomenon commonly observed in IHH (Bouilly et al, 2018;Louden et al, 2021;Xu et al, 2017). The male patients in Family-B, Family-H, and Family-L had cryptorchidism, indicating severe congenital hypogonadism.…”

Section: Resultssupporting

confidence: 64%

“…According to olfactory function, IHH is divided into two major forms, normal sense of smell (normosmic IHH, nIHH) and inability to smell, anosmia, defined as Kallmann syndrome (KS). Although nearly 50 genes have been reported to be associated with IHH(Howard & Dunkel, 2019; Louden et al, 2021), they account for only 50% of all cases indicating that other associated genes remain to be discovered. Delineating new genes involved in the development and/or function of GnRH neurons is relevant for understanding the basis of IHH pathogenesis in humans.…”

Section: Introductionmentioning

confidence: 99%

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POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

Cho

Gürbüz

Stamou

et al. 2022

Preprint

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Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent pubertal development and infertility, often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants inPOU6F2. POU6F2encodes two distinct isoforms. In mouse, pituitary and gonads expressed both isoforms, but only isoform1 was detected in GnRH cells. Although the function of isoform2 is well known, using bioinformatics and cells assays on a human-derived GnRH cell line, we demonstrate isoform1 can also act as a transcriptional regulator, decreasingGNRH1expression. The impact of twoPOU6F2variants (MT1 and MT2) was then examined. MT1, but not MT2, reduced transcriptional activity of either isoform, preventing Hes5 promoter activation by isoform2 and repression of GnRH transcripts by isoform1. GnRH transcription increases as the cells migrate into the brain. Augmentation earlier can disrupt normal GnRH cell migration, consistent with POU6F2 variants contributing to IHH pathogenesis.

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Section: Resultssupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

Cho

Gürbüz

Stamou

et al. 2022

Preprint

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“…The recognition of digenic and oligogenic inheritance has important implications for genetic counseling and risk assessment [12]. Genetic counselors play a vital role in providing information and support to individuals and families affected by genetic disorders.…”

Section: Genetic Counseling and Risk Assessmentmentioning

confidence: 99%

Digenic or oligogenic mutations in presumed monogenic disorders: A review

et al. 2023

Self Cite

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Monogenic disorders are traditionally attributed to the presence of mutations in a single gene. However, recent advancements in genomics have revealed instances where the phenotypic expression of apparently monogenic disorders cannot be fully explained by mutations in a single gene alone. This review article aims to explore the emerging concept of digenic or oligogenic inheritance in seemingly monogenic disorders. We discuss the underlying mechanisms, clinical implications, and the challenges associated with deciphering the contribution of multiple genes in the development and manifestation of such disorders. We present relevant studies and highlight the importance of adopting a broader genetic approach in understanding the complex genetic architecture of these conditions.

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“…In this review, we also provide insights into genes that are still not recognized as CHH causative genes but have been described to play a role in GnRH neuron biology and found to be mutated in patients with CHH or overlapping syndromes. The causative CHH genes associated with pituitary development and function (e.g., FSHB, GATA2, GLI2, GNRHR, HESX1, LHB, LHX3/4, OTX2, PITX2, PROP1 and SOX2/3; reviewed in [41,63]) are not discussed in this review. In humans, the hypophysiotropic form of GnRH decapeptide is encoded by GNRH1 gene (chr 8p21.2) and, although variants in this gene are expected to be disease causing, GNRH1 variants are rare (2% of normosmic CHH cases) [41].…”

Section: Genetics Of Chhmentioning

confidence: 99%

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

Oleari

Massa

Cariboni

et al. 2021

IJMS

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Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

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Genetics of hypogonadotropic Hypogonadism—Human and mouse genes, inheritance, oligogenicity, and genetic counseling

Cited by 18 publications

References 187 publications

POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

Digenic or oligogenic mutations in presumed monogenic disorders: A review

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

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